1. Field of the Invention
The present invention relates to preparation of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®). Particularly, this invention relates to the preparation of duloxetine hydrochloride.
2. Description of Related Art
(S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®) is used as an antidepressant drug in the form of hydrochloride salt. US2007/0167636 discloses a process for the preparation of duloxetine by reacting (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol with 1-fluoronaphthalene, in the presence of potassium hydroxide and in a mixture of DMSO and toluene. In this process, the reaction is carried out in a mixed solvent system of toluene and DMSO, preferably with greater ratio by volume. However, carrying out the reaction in this solvent system is time consuming. Moreover, more working procedure is required in order to obtain a product of high quality.
In addition, WO2007/148103 discloses a method for preparing crystalline duloxetine hydrochloride. In this case, the duloxetine is purified by being crystallized from an ethanol solution with 20% hydrochloric acid as the chlorinating agent, such that crystalline duloxetine hydrochloride with about 55% yield is obtained. Furthermore, U.S. Pat. No. 5,362,886 discloses that duloxetine hydrochloride is obtained by adding concentrated hydrochloric acid to a solution of duloxetine base in ethyl acetate. However, the preparation of duloxetine hydrochloride by using hydrochloride acid as the chlorinating agent results in low yield of duloxetine hydrochloride due to high solubility of duloxetine hydrochloride in water.
WO2007/148102 further provides a method for the preparation of crystalline duloxetine hydrochloride, in which gaseous hydrochloride is introduced into an organic solution of duloxetine. However, the gaseous hydrochloride is dangerous to handle.